Neuroprotection by S-nitrosoglutathione of brain dopamine neurons from oxidative stress.
The proposed anti- and pro-oxidant effects of nitric oxide (NO) derivatives, such as S-nitrosoglutathione (GSNO) and peroxynitrite, were investigated in the rat nigrostriatal dopaminergic system. Intranigral infusion of freshly prepared GSNO (0-16.8 nmol, i.n.) prevented iron-induced (4.2 nmol, i.n.) oxidative stress and nigral injury, reflected by a decrease in striatal dopamine levels. This neuroprotective effect of GSNO was verified by ex vivo imaging of brain dopamine uptake sites using 125I-labeled RTI-55. In addition, in vitro data indicate that GSNO concentration-dependently inhibited iron-evoked hydroxyl radical generation and brain lipid peroxidation. In this iron-induced oxidant stress model, GSNO was approximately 100-fold more potent than the antioxidant glutathione (GSH). Light-exposed, NO-exhausted GSNO produced neither antioxidative nor neuroprotective effects, which indicates that NO may mediate at least part of GSNO's effects. Moreover, GSNO completely (and GSH only partially) inhibited the weak pro-oxidant effect of peroxynitrite, which produced little injury to nigral neurons in vivo. This study provides relevant in vivo evidence suggesting that nanomol GSNO can protect brain dopamine neurons from iron-induced oxidative stress and degeneration. In conclusion, S-nitrosylation of GSH by NO and oxygen may be part of the antioxidative cellular defense system.
Rauhala
P
P
Unit on Neurodegeneration and Neuroprotection, Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892-1264, USA.
Lin
A M
AM
Chiueh
C C
CC
D000818:Animals; D001345:Autoradiography; D019343:Citric Acid; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism*; D005296:Ferrous Compounds / Q000633:toxicity; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007263:Infusions, Parenteral; D007457:Iodine Radioisotopes; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009566:Nitrates / Q000633:toxicity; D009603:Nitroso Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
D005296:Ferrous Compounds; D007457:Iodine Radioisotopes; D018696:Neuroprotective Agents; D009566:Nitrates; D009603:Nitroso Compounds; D016877:Oxidants; C039642:peroxynitric acid; D019343:Citric Acid; C016600:ferrous citrate; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D026422:S-Nitrosoglutathione; D005978:Glutathione; D003042:Cocaine; D004298:Dopamine